title: Design, synthesis, and evaluation of multitarget-directed resveratrol derivatives for the treatment of Alzheimer's disease.
abstract: A series of multitarget-directed resveratrol derivatives was designed and synthesized for the treatment of Alzheimer's disease (AD). In vitro studies indicated that most of the target compounds exhibit significant inhibition of self-induced β-amyloid (Aβ) aggregation and Cu(II)-induced Aβ1-42 aggregation and acted as potential antioxidants and biometal chelators. In particular, compounds 5d and 10d are potential lead compounds for AD therapy (5d, IC50 = 7.56 μM and 10d, IC50 = 6.51 μM for self-induced Aβ aggregation; the oxygen radical absorbance capacity assay using fluorescein (ORAC-FL) values are 4.72 and 4.70, respectively). Moreover, these compounds are capable of disassembling the highly structured Aβ fibrils generated by self- and Cu(II)-induced Aβ aggregation. Furthermore, 5d crossed the blood-brain barrier (BBB) in vitro and did not exhibit any acute toxicity in mice at doses of up to 2000 mg/kg. Taken together, the data indicate that 5d is a very promising lead compound for AD.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou, 510006, China.
authors.forename: Chuanjun
authors.initials: C
authors.lastname: Lu
authors.forename: Yueyan
authors.initials: Y
authors.lastname: Guo
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.forename: Zonghua
authors.initials: Z
authors.lastname: Luo
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Luo
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.forename: Ling
authors.initials: L
authors.lastname: Huang
authors.forename: Xingshu
authors.initials: X
authors.lastname: Li
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis* / Q000627:therapeutic use; D001812:Blood-Brain Barrier; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis; D007464:Clioquinol / Q000031:analogs & derivatives; D015195:Drug Design; D006801:Humans; D051379:Mice; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D008996:Monoamine Oxidase Inhibitors; D010446:Peptide Fragments; D013267:Stilbenes; C075222:amyloid beta-protein (1-42); D007464:Clioquinol; D000077185:Resveratrol